Abstract

1538

Hepatocellular carcinoma (HCC) associated with chronic liver disease evolves from precancerous lesions and early HCC to a progressed form. Despite the demonstrated importance of cell-cycle regulators in tumor biology, there have not been any studies on cell-cycle regulators in precancerous lesions and early HCC. Recent information indicates that decreased expressions of p27 protein are associated with high aggressiveness and poor prognosis in a large variety of cancers, including classical HCC. Expression of p27, and Skp2 (S-phase kinase-interacting protein) and Jab1 (Jun activation domain-binding protein-1), two key molecules in the degradation of p27, was analyzed by immunohistochemistry in surgically resected 8 adenomatous hyperplasia (dysplastic nodules), 15 early HCCs, and 105 classical HCCs. Ki-67 labeling index (LI) increased significantly according to the stepwise progression of hepatocarcinogenesis. Immunohistochemistry revealed no p27 expression in the majority of hepatocytes from normal and cirrhotic liver, whereas positive staining for p27 protein was found in 62.5% (5/8) and 86.7% (13/15) of adenomatous hyperplasia and early HCC, respectively. The p27 LI was 37.8% in adenomatous hyperplasia, 43.7% in early HCC, 38.4% in well differentiated HCC, 62.8% in moderately differentiated HCC and 43.2% in poorly differentiated HCC. Real-time quantitative reverse transcriptional polymerase chain reaction (RT-PCR) confirmed these findings. Skp2 LI increased significantly according to the stepwise progression of hepatocarcinogenesis. A significant-negative correlation was found between p27 LI and Skp2 LI in classical HCC. High Skp2 expression was frequent especially in HCCs with poor differentiation. On the other hand, Jab1 was overexpressed in 50.0% (4/8) and 46.7% (7/15) of adenomatous hyperplasia and early HCC, respectively, as well as classical HCC. The Skp2 and Jab1 LI in 32 classical HCCs with microscopic portal vein invasion were significantly higher than 73 classical HCCs without microscopic portal vein invasion. We demonstrate for the first time that p27 is overexpressed from the very early stages of hepatocarcinogenesis, suggesting that p27 may be a potential diagnostic marker and treatment target for precancerous lesions and early HCC. Furthermore, Skp2 might contribute to dedifferentiation of HCC via the degradation of p27.